EP3405485B1 - Endothelin-1 receptor based endothelin-1 sponge - Google Patents

Endothelin-1 receptor based endothelin-1 sponge Download PDF

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EP3405485B1
EP3405485B1 EP16702808.3A EP16702808A EP3405485B1 EP 3405485 B1 EP3405485 B1 EP 3405485B1 EP 16702808 A EP16702808 A EP 16702808A EP 3405485 B1 EP3405485 B1 EP 3405485B1
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endothelin
binding domains
amino acid
ligand
receptor ligand
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EP3405485A1 (en
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Arjun Jain
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2318/00—Antibody mimetics or scaffolds
    • C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • Endothelin-1 is a vasoactive peptide synthesized and secreted by a diverse range of cells, and thus implicated in signalling events in a wide variety of target tissues (Nelson et al. 2003). Endothelin-1 plays a key role in physiological functions. However, under elevated levels, endothelin-1 induces pathology and as such is implicated in a host of different diseases, including neurodegenerative disorders, cardiovascular diseases, as well as pregnancy disorders like preeclampsia (Jain 2013, Jain et al. 2012). Given that a key feature of these diseases is elevated endothelin-1 levels, one proposed strategy of therapeutic intervention is targeting the increased levels of endothelin-1.
  • endothelin-1 antagonists capable of binding endothelin-1 to form a non-functional complex
  • Endothelin-1 exerts its effects by binding to the endothelin A (ETA) and endothelin B (ETB) receptors, two highly homologous cell-surface proteins that belong to the G-protein- coupled receptor superfamily (Karet and Davenport 1994).
  • the two receptors share about 60% similarity in the primary structure (Nelson et al. 2003), i.e. both receptors exhibit a high polypeptide sequence identity with each other. Nevertheless, the two receptors show a clear distinction in ligand binding selectivity based on their ligand-binding domains.
  • Endothelin-1 binding to the ETA receptor is thought to require the ETA receptor N-terminus loop, extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), intracellular loop 3 (ICL3), extracellular loop 3 (ECL3) and the C-terminal domain (Adachi et al. 1993). Amino acid sequences of these ETA receptor ligand-binding domains are given in Figure 1 .
  • ECL1 A 5 amino acid sequence (140 - Lys Leu Leu Ala Gly - 144) in ECL1 has been implicated as the most important element required for ligand binding.
  • Orry et al. (2000) also constructed a model of interaction of the ET-1 peptide with the ETA receptor, where ET-1 makes contacts with both the N-terminal receptor domain and 2 different extracellular loops.
  • C-terminal 8 amino acid residues located in close proximity to the seventh transmembrane region and the C-terminal 16 amino acid residues in the third intracellular loop are important for endothelin-1 binding (Adachi et al. 1993).
  • Endothelin-1 binding to the ETB receptor requires the 39 amino acids between Pro93 in the N-terminal domain and Cys131 in the first intracellular loop of the ETB receptor (Klammt et al. 2007).
  • the 12 amino acids from Ser390 to Leu401 in the proximal cytoplasmic tail are necessary to maintain the ligand-binding site in an active form (Wada et al. 1994).
  • the present invention provides amino acid sequences of fusion polypeptides capable of binding endothelin-1 to form a nonfunctional complex comprising:
  • An object of the present invention is the production of endothelin-1 antagonists that are useful in the treatment of endothelin-1 -related diseases or disorders.
  • Another object of the invention is the use of the disclosed endothelin-1 antagonists for the treatment of endothelin-1 -related diseases or disorders.
  • an endothelin-1 antagonist described herein may be used for the treatment of preeclampsia, cardiovascular diseases or neurodegenerative disorders.
  • Another object of the invention is the construction of several specific endothelin-1 antagonists, termed endothelin-1 sponge, each having different sequences but all being capable of blocking the binding of endothelin-1 to its receptor/s, thus functioning as endothelin-1 antagonists

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Description

    Background:
  • Endothelin-1 is a vasoactive peptide synthesized and secreted by a diverse range of cells, and thus implicated in signalling events in a wide variety of target tissues (Nelson et al. 2003). Endothelin-1 plays a key role in physiological functions. However, under elevated levels, endothelin-1 induces pathology and as such is implicated in a host of different diseases, including neurodegenerative disorders, cardiovascular diseases, as well as pregnancy disorders like preeclampsia (Jain 2013, Jain et al. 2012). Given that a key feature of these diseases is elevated endothelin-1 levels, one proposed strategy of therapeutic intervention is targeting the increased levels of endothelin-1. To this end, fusion polypeptides capable of binding endothelin-1 to form a non-functional complex would serve as endothelin-1 antagonists. The construction of these endothelin-1 antagonists, termed endothelin-1 sponge, would require fusing the endothelin-1 receptor(s) ligand-binding domains to the Fc portion of human IgG1.
  • Endothelin-1 exerts its effects by binding to the endothelin A (ETA) and endothelin B (ETB) receptors, two highly homologous cell-surface proteins that belong to the G-protein- coupled receptor superfamily (Karet and Davenport 1994). The two receptors share about 60% similarity in the primary structure (Nelson et al. 2003), i.e. both receptors exhibit a high polypeptide sequence identity with each other. Nevertheless, the two receptors show a clear distinction in ligand binding selectivity based on their ligand-binding domains.
    • Endothelin-1 binding to the ETA receptor:
  • Endothelin-1 binding to the ETA receptor is thought to require the ETA receptor N-terminus loop, extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), intracellular loop 3 (ICL3), extracellular loop 3 (ECL3) and the C-terminal domain (Adachi et al. 1993). Amino acid sequences of these ETA receptor ligand-binding domains are given in Figure 1.
  • A 5 amino acid sequence (140 - Lys Leu Leu Ala Gly - 144) in ECL1 has been implicated as the most important element required for ligand binding. In addition, both ECL2 and ECL3, including the flanking transmembrane regions, were found to play an important role in ligand selection.
  • Orry et al. (2000) also constructed a model of interaction of the ET-1 peptide with the ETA receptor, where ET-1 makes contacts with both the N-terminal receptor domain and 2 different extracellular loops.
  • Further, the C-terminal 8 amino acid residues located in close proximity to the seventh transmembrane region and the C-terminal 16 amino acid residues in the third intracellular loop are important for endothelin-1 binding (Adachi et al. 1993).
    • Endothelin-1 binding to the ETB receptor:
  • Endothelin-1 binding to the ETB receptor requires the 39 amino acids between Pro93 in the N-terminal domain and Cys131 in the first intracellular loop of the ETB receptor (Klammt et al. 2007). In addition, the 12 amino acids from Ser390 to Leu401 in the proximal cytoplasmic tail are necessary to maintain the ligand-binding site in an active form (Wada et al. 1994).
  • Further, it has been suggested that the 60 amino acids sequence from IIe138 to IIe197 located in transmembrane domains 2 and 3 (TM2+3) might also be important for ligand binding. Amino acid sequences of these ETB receptor ligand-binding domains are given in Figure 2.
    • Constructing endothelin-1 sponge:
    1. 1. Endothelin-1 sponge could be constructed by fusing the above mentioned ETA receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 3).
    2. 2. Endothelin-1 sponge could be constructed by fusing the above mentioned ETB receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc portion of human IgG1 (Figure 4).
    3. 3. Endothelin-1 sponge could be constructed by fusing the ETB receptor ligand-binding domains inline with the ETA receptor ligand-binding domains into a fusion polypeptide that can then be fused to the Fc potion of human IgG1 (Figure 5).
  • The present invention provides amino acid sequences of fusion polypeptides capable of binding endothelin-1 to form a nonfunctional complex comprising:
    1. a) ETA receptor ligand-binding domains
    2. b) ETB receptor ligand-binding domains
    fused to the Fc portion of human IgG1. SUMMARY OF THE INVENTION
  • An object of the present invention is the production of endothelin-1 antagonists that are useful in the treatment of endothelin-1 -related diseases or disorders.
  • Another object of the invention is the use of the disclosed endothelin-1 antagonists for the treatment of endothelin-1 -related diseases or disorders. For example, an endothelin-1 antagonist described herein may be used for the treatment of preeclampsia, cardiovascular diseases or neurodegenerative disorders.
  • Another object of the invention is the construction of several specific endothelin-1 antagonists, termed endothelin-1 sponge, each having different sequences but all being capable of blocking the binding of endothelin-1 to its receptor/s, thus functioning as endothelin-1 antagonists
    • DESCRIPTION OF THE FIGURES
    • Figure 1. ETA receptor ligand-binding domains
    • Figure 2. ETB receptor ligand-binding domains
    • Figure 3. Proposed design of ET-1 sponge based on ETA receptor ligand-binding domains
    • Figure 4. Proposed design of ET-1 sponge based on ETB receptor ligand-binding domains
    • Figure 5. Proposed design of ET-1 sponge based on ETA and ETB receptors' ligand-binding domains
    • Figure 6A-C. SEQ ID NO: 1, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1
    • Figure 7A-C. SEQ ID NO: 2, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1
    • Figure 8A-C. SEQ ID NO: 3, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 and C-terminus, fused to the Fc portion of human IgG1
    • Figure 9A-C. SEQ ID NO: 4, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ECL2, ICL3 (16 amino acids) and C-terminus (8 amino acids), fused to the Fc portion of human IgG1
    • Figure 10A-C. SEQ ID NO: 5, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3, ECL3 and C-terminus, fused to the Fc portion of human IgG1
    • Figure 11A-C. SEQ ID NO: 6, comprising ETA receptor (ETAR) ligand-binding domains, including the N-terminus, ECL1, ICL3 (16 amino acids), ECL3 and C-terminus (8 amino acids), fused to the Fc portion of human IgG1
    • Figure 12A-B. SEQ ID NO: 7, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1 and C-terminus, fused to the Fc portion of human IgG1
    • Figure 13A-C. SEQ ID NO: 8, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus, ICL1, TM2 + 3 and C-terminus, fused to the Fc portion of human IgG1
    • Figure 14A-B. SEQ ID NO: 9, comprising ETB receptor (ETBR) ligand-binding domains, including the N-terminus and ICL1, fused to the Fc portion of human IgG1

Claims (7)

  1. A fusion polypeptide comprising:
    (i) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 6A-C;
    (ii) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 7A-C;
    (iii) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 8A-C;
    (iv) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 9A-C;
    (v) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 10A-C;
    (vi) the amino acid sequence of the endothelin A receptor ligand binding domains of Figures 11A-C;
    (vii) the amino acid sequence of the endothelin B receptor ligand binding domains of Figures 12A-B;
    (viii) the amino acid sequence of the endothelin B receptor ligand binding domains of Figures 13A-C; or
    (ix) the amino acid sequence of the endothelin B receptor ligand binding domains of Figures 14A-B.
  2. A multimer of the fusion polypeptide of claim 1.
  3. A recombinant nucleic acid molecule encoding the fusion polypeptide of claim 1.
  4. A vector comprising the recombinant nucleic acid molecule of claim 3.
  5. The vector of claim 4, wherein the nucleic acid molecule encoding the fusion polypeptide is operatively linked to an expression control sequence.
  6. A composition comprising the multimer of claim 2.
  7. The composition of claim 6, wherein the multimer is a dimer.
EP16702808.3A 2015-03-01 2016-01-22 Endothelin-1 receptor based endothelin-1 sponge Active EP3405485B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB201503453A GB201503453D0 (en) 2015-03-01 2015-03-01 Endothelin-1"sponge"
GBGB1507043.6A GB201507043D0 (en) 2015-03-01 2015-04-24 Endothelin-1 receptor(s) based endothelin-1 sponge
PCT/IB2016/050337 WO2016139543A1 (en) 2015-03-01 2016-01-22 Endothelin-1 receptor based endothelin-1 sponge

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EP3405485B1 true EP3405485B1 (en) 2021-01-13

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US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US6077835A (en) 1994-03-23 2000-06-20 Case Western Reserve University Delivery of compacted nucleic acid to cells
KR970029803A (en) 1995-11-03 1997-06-26 김광호 Precharge Circuit of Semiconductor Memory Device
US6472179B2 (en) 1998-09-25 2002-10-29 Regeneron Pharmaceuticals, Inc. Receptor based antagonists and methods of making and using
US6927044B2 (en) 1998-09-25 2005-08-09 Regeneron Pharmaceuticals, Inc. IL-1 receptor based cytokine traps
US6281005B1 (en) 1999-05-14 2001-08-28 Copernicus Therapeutics, Inc. Automated nucleic acid compaction device
MXPA01012630A (en) 1999-06-08 2002-07-22 Regeneron Pharma Modified chimeric polypeptides with improved pharmacokinetic properties.
JP2005525404A (en) 2002-05-01 2005-08-25 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Methods of using cytokine antagonists to treat HIV infection and AIDS
ES2412005T3 (en) 2005-04-15 2013-07-09 The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services Treatment and prevention of inflammatory bowel disease involving IL-13 and NKT cells
JP2012050368A (en) * 2010-08-31 2012-03-15 Sekisui Chem Co Ltd Vector, recombinant cell, and method for presenting protein on surface of cell

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CN109071677A (en) 2018-12-21
US20190016773A1 (en) 2019-01-17
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GB201503453D0 (en) 2015-04-15
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